Introduction: Apomorphine (Apo),
a dopamine (DA) receptor agonist in animals and
man, induces yawning in a variety of species
including humans, by stimulating central D2
receptors. Systematic studies of Apo-induced
yawning in man have been few. As a result of
unexpected circumstances, we were obliged to
change the time of our experiments on yawning
from the morning to the afternoon. On inspection
of our findings, we observed that when Apo was
given in the aftemoon, the yawning response was
less. We now report our results.

Materials and Methods : Subjects : Two
separate groups of normal male volunteers on no
medication who were physically healthy, based on
medical history, physical examination, routine
biochemical screening, hemogram, urinalysis and
ECG, and who gave their informed consent served
as subjects. All volunteers were asked to keep
their sleep habits and their caffeine intake
constant at least 2 weeks prior to commencing
the study. Shift workers were excluded. Subjects
were asked to refrain from over-thecounter drugs
such as aspirin as well as alcohol for at least
72 h prior to testing. Subjects using
recreational drugs were excluded. The ApoAM
group, who were investigated in the morning,
consisted of 11 men (mean age 25.5. range 19-31
vearsland the Apo-PM group, who were
investigated in the afternoon, consisted of 16
men (mean age 27.6: range 20-35 years).

Procedures : Subjects were informed
that they would be tested on three separate
occasions. and that on two of these they would
receive placebo (physiological saline) and on
one occasion Apo HCI (7 pg/kg s.c.). The first
session. conducted under single blind
conditions, was an adaptation session in which
the subjects received placebo. Data from this
session were discarded. The remaining two
sessions were conducted under double-blind
conditions in a balanced design. The Apo AM
group arrived at the laboratory after an
overnight fast between 8.00 h and 8.30 h.
Following attachment of the sensors, one to the
forchead just below the hairline and the other
under the chin. the subjects rested quietly in
the supine position for 30 min. Apo or placebo
were administered at 9.00 h. The Apo-PM group
arrived ai the laboratory between 12-00 h and
12.30 h. They were allowed to eat breakfast but
fasted after 9.00 h. After resting supine for 30
min Apo or placebo was administered at 13.00 h.
Following injection, yawning was monitored over
a 60-min period with a polygraph by recording
displacement of the lowerjaw using a pair of
linearized magnetometers as described
previously.

Data Analysis : Yawns were identified
by inspection of the tracing by two independent
raters blind to the treatment code. The yawns
were readily distinguished from swallowing,
coughing and sneezing, and there was complete
concordance between the raters. The number of
yawns were tallied and differences between
treatments and between groups were analyzed
using the Mann-Whitney test for unpaired data
and the Wilcoxon sign-rank test for paired data.
Data are presented as the mean ± standard
deviation (SD).

Results : Apo increased yawning when
given in the morning: Apo-AM 18.3 ± 12.5
(mean ± SD) versus placebo-AM 10.7 ±
8.5 (p < 0.02). In contrast, Apo
administration in the afternoon showed no
significant increase versus placebo: Apo-PM 6.1
± 5.9 versus placebo-PM 4.1 ± 4.1 (p =
NS). The number of yawns after Apo in the
morning was significantly greater than after Apo
given in the afternoon (p < 0.01).
Placebo-induced yawning was significantly
greater in the morning than in the afternoon (p
< 0.025). When the placebo response was
subtracted from the Apo response for each
individual, the morning-afternoon difference
after Apo remained significant (p <
0.02).

Discussion : Yawning is under the
control of several neurotransmitters and
neuropeptides subserved by different neural
mechanism. Yawning induced by Apo is mediated by
activation of central D2 receptors located in
the paraventricular nucleus of the hypothalamus
which contains nerve endings from the
incertohypothalamic DA system. Nitric oxide
formation may be involved in the process as an
intracellular messenger. Central muscarinic and
oxytocinergic links are important mediators of
Apo effects. Activation of D 1 receptors has a
facilitatory role. DA autoreceptors have been
implicated in the yawning response but more
recent evidence points to the stimulation of
postsynaptic DA receptors in both animals and
man.

In the rat, there is a circadian variation in
tyrosine hydroxylase activity, DA turnover, DA
levels and number of DA receptors. A change in
receptor number could explain our present
rindings of a difference in yawning response
depending on time of day of Apo administration.
In the rodent, a time-of-day effect on the
yawning response to Apo has been described which
is linked to the light-dark cycle. This diurnal
variation is also noted with spontaneous
yawning.

In the rat, fasting for 24 h influences
Apo-induced yawning. In the present study, both
groups of men were fasting, but the Apo-AM group
fasted longer. Accordingly, this difference may
have influenced our findings. In the rat,
fasting decreases the yawning response to Apo.
However, the influence of fasting on yawning in
man is unknown. Our results show an increase
in yawning in subjects tested in the
morning, ie. those fasting longer. Constant
stress and intermittent stress differentially
affect Apo-induced yawning in the rat. The
response is also influenced by paradoxical sleep
deprivation. The influence of such factors in
man is unknown. The yawning response to both Apo
and placebo decreases with age. In the present
study, there was no significant difference in
age between the two groups of subjects.

In man, psychological factors such as
boredom, lack of stimulus interest, suggestion
induced by observing, reading and thinking about
yawning may induce yawning. Baenninger,
however, found little influence of boredom and
contagiousness of yawning. Recently, Baenninger
et al. showed that yawning frequency was
unrelated to the prior amount of sleep, times of
awaking or retiring, but was consistent with the
view that yawning is predictive of an
increase in activity level. The response to
placebo under experimental conditions noted
previously and confirmed in the present study
indicates that suggestion plays some role in
spontaneous yawning. It is possible that
subjects tested in the morning were more drowsy
and hence the increase in yawning. Though
tiredness and drowsiness have anecdotally been
associated with yawning, a relationship between
drowsiness and yawning frequency has not been
observed experimentally. In a field study of
taxi drivers Sakai and Takashi reported an
increase in yawning burst especially when the
subjects were feeling drowsy. Drowsiness,
however, was not quantified.